Pathogenesis

Scleroderma is an autoimmune connective tissue disease whose hallmark is excessive collagen deposited around capillaries and in affected tissues, such as the skin, lungs, kidney and esophagus. The etiology is unknown, but its pathogenesis involves an activated immune system, abnormal vascular endothelium and an exaggerated production of fibroblasts that results in abnormal collagen buildup.

Collagen is the major component of connective tissue found in skin, tendons, joints, ligaments and around major organs. Collagen is the basic substance that forms scar tissue, an indispensable part of the repair process of the body. However, an overproduction of collagen interrupts vital systems by replacing functioning cells with "scars."

When this process goes on in the lungs, for example, it results in pulmonary fibrosis, leading to the disruption of the oxygen/carbon dioxide exchange cycle with subsequent changes in pulmonary function. It also can affect the pulmonary vasculature, resulting in pulmonary hypertension - or it can affect both components of the lung more or less simultaneously, the alveoli (fibrosis) and the vessels (pulmonary hypertension).¹

There is an interrelationship among immune, vascular, endothelial, fibroblast and genetic processes that results in the manifestations of scleroderma.² If there is a genetic background and an external stimulus, the immune system is activated, resulting in vascular injury, fibroblast proliferation and collagen deposition in skin and, often, internal organs.³

Examples of external stimuli include cold (in the case of Raynaud's phenomenon), toxic substances such as organic solvents and silica dust, and various kinds of organ transplantation. Although these have been implicated in cases of scleroderma and scleroderma-like disease, none has been shown to be the singular cause of the disease.

More than 90 percent of people with scleroderma have Raynaud's phenomenon. The vasospasm manifested in Raynaud's can stimulate the immune system, resulting in a mini-feedback loop in which immune activation results in vascular damage (or vice versa).¹ The vasospasm observed in the fingers of people with Raynaud's has also been found in the lungs and kidneys of scleroderma patients by radiographic examination.¹

There is generally no specific genetic predisposition to scleroderma, although there is an human leukocyte antigen-associated increase in prevalence.⁴ The presence of other autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and Graves' disease in relatives of the scleroderma patient has been noted.^1,5

Epidemiology

A disease variable in presentation and unusual in occurrence like scleroderma makes epidemiological surveys complex and difficult. As more research is being done on more patients, more reliable data has emerged, including the following:

• Women outnumber men by approximately 5 to 1, (range 3:1 to 8:1).^1,6

• Mean age range is 40-50.¹

• With treatment, the 5-year survival rate is over 80 percent, although morbidity is considerable. In the worst 10-15 percent, the 5-year mortality is 50 percent.

• The most recent study reveals that the overall prevalence in adults is 240/million or about 300,000.⁶

• Blacks have more severe disease more frequently than whites, Asians and Hispanics.⁵

• Twin studies have indicated that the likelihood of twins having scleroderma is 6 percent. This is higher than the general population but not high enough (100 percent) to indicate a pure genetic etiology.⁵


Classification

The word scleroderma means, literally, "hard skin." French physicians named it in the late 1700s. There are two main forms and a third group of scleroderma-like disorders that share some of the symptoms of the other two.⁵

Localized scleroderma (most often found in children):

• Morphea (patches of thickened skin.)

• Linear (thickened skin tethered to underlying muscle and bone.)

• Scleroderma en coup de sabre ("cut of the saber," linear scleroderma of the head and face only.)

Systemic scleroderma:

• Limited scleroderma (was also called CREST, an acronym for Calcinosis, Raynaud's, Esophageal dysfunction, Sclerodactyly and Telangiectasias; this acronym should be discarded as inaccurate.)

• Diffuse scleroderma (extensive skin thickening proximal to the elbows and knees along with internal organ involvement.)

• Scleroderma sine sclerosis (Raynaud's phenomenon and internal involvement without skin thickening.)